A model for long-term transgene expression in spinal cord regeneration studies.

In order to determine the suitability of first generation adenoviral vectors for gene delivery into spinal cord white matter, four different titres of beta-galactosidase-expressing adenovirus were injected into spinal cord white matter of adult rats. At titres > or =106 p.f.u., transgene expression was extensive but severe tissue damage was observed in the form of axon degeneration, demyelination and astrocyte loss. When < or = 105 p.f.u. were injected, only low levels of axon degeneration and demyelination were observed. beta-Galactosidase activity was detectable at 72 days and did not diminish significantly with time. The immune response in the spinal cord to 105 p.f.u. over 72 days was minimal, and indistinguishable from that to injection of buffer. A prominent immune response was observed when 107 p.f.u. was injected into the spinal cord of PVG rats, and when 105 or 107 p.f.u. was injected into AO rats. These results indicate that the immune response in PVG rats to betagal-expressing adenovirus is both strain and titre dependent. First generation adenoviral vectors, therefore, induce moderate and long-lived transgene expression with minimal tissue damage and immune response when an appropriate titre is injected into the low responder PVG rat strain, providing a suitable model for assessing the effect of gene delivery in models of spinal cord injury.